Pathways underlying recovery of injured urethral sphincter and a novel regenerative biomaterial intervention

项目摘要 横纹外尿道括约肌功能障碍是压力性尿失禁的最强预测因子， 定义为在无膀胱的情况下由于腹内压增加而导致的不自主排尿 收缩。压力性尿失禁影响大约1/2的妇女在他们的生活中的某个时候。的 慢性压力性尿失禁的发展背后的主要煽动事件已经明确 被确定为阴道分娩期间妇女持续的泌尿系统损伤。这 令人震惊的普遍情况大大降低了生活质量，导致严重的发病率， 这给个人和社会带来了巨大的经济负担。尽管如此，预防策略 几乎不存在，可用的治疗是延迟和补偿性的，因为它们不直接针对 潜在的病理生理学上述情况很大程度上是由于我们对这些途径的理解， 导致尿道外括约肌的内在肌肉成分在出生损伤后失效 有限公司此外，流行的临床前研究没有利用生物学相关的妊娠动物模型 产伤。为了解决现有的未满足的临床需求和知识差距，我们组装了一个交叉- 具有多样化但互补的专业知识的学科团队，在以下两个方面的接口执行当前项目： 基础科学、生物材料开发和转化医学。我们将使用一种经过验证的 相关妊娠临床前模型，以研究多个时间点的结构、分子和细胞事件 在产伤后横纹外尿道括约肌的恢复连续体上的点。这些基本 过程将告知新的微创组织的开发和关键时间， 预防和治疗尿道肌肉功能障碍的工程疗法。具体来说，我们将测试一个 一种新的促再生骨骼肌特异性可注射细胞外基质水凝胶， 脱细胞猪骨骼肌预防和逆转外尿道适应不良恢复 产伤后的括约肌。总的来说，这项创新的研究将提供基本的知识， 参与调节外尿道括约肌再生的生物学过程，以及 对低成本脱细胞微创治疗的作用进行全面的功能相关评估 再生疗法，以抵消现有的流行性尿失禁。

PROJECT SUMMARY Dysfunction of the striated external urethral sphincter is the strongest predictor of stress urinary incontinence, defined as involuntary loss of urine due to increased intraabdominal pressure in the absence of bladder contraction. Stress urinary incontinence affects approximately 1 in 2 women at some point in their lives. The primary inciting event behind the development of chronic stress urinary incontinence has been unequivocally identified as injury to the urinary continence mechanism sustained by women during vaginal deliveries. This astoundingly prevalent condition dramatically decreases quality of life, causes significant morbidity, and is associated with large economic burden to the individuals and society. Despite this, preventative strategies are almost non-existent, and the available treatments are delayed and compensatory as they do not directly target the underlying pathophysiology. The above is largely due to the fact that our understanding of the pathways that lead to failure of the intrinsic muscular components of the external urethral sphincter following birth injury remains limited. Furthermore, the prevailing preclinical studies do not utilize biologically relevant pregnant animal model of birth injury. To address the existing unmet clinical need and knowledge gaps, we assembled a cross- disciplinary team with diverse but complimentary expertise to execute the current project at the interface between basic science, biomaterial development, and translational medicine. We will use a validated and biologically relevant pregnant pre-clinical model to investigate structural, molecular, and cellular events at multiple time points across a recovery continuum of the striated external urethral sphincter following birth injury. These basic processes will inform the development of and the critical time to deliver new, minimally invasive tissue- engineered therapy for the prevention and treatment of urethral muscle dysfunction. Specifically, we will test a novel pro-regenerative skeletal muscle-specific injectable extracellular matrix hydrogel, derived from decellularized porcine skeletal muscles, in preventing and reversing maladaptive recovery of the external urethral sphincter following birth injury. Collectively, this innovative study will provide fundamental knowledge of the biological processes involved in the regulation of external urethral sphincter muscle regeneration, and comprehensive functionally relevant assessments of the role of low-cost acellular minimally invasive regenerative therapy to counteract the existing epidemic of urinary incontinence.